The proposed project aims to investigate how maternal stress during pregnancy, maternal inflammation during pregnancy and fetal hypoxia (lack of oxygen to the fetus) influence the risk of symptoms of depression during adolescence in offspring. A secondary aim is to map trajectories of how these prenatal risk factors result in a cascade of events, leading to altered developmental trajectories in emotional, cognitive, and behavioral outcomes during childhood and subsequent depression during adolescence. The proposed project is based on a large birth cohort study, the Child Health and Development Study (CHDS), that followed women prospectively throughout their pregnancies from 1959-1966 and acquired detailed information on the mothers' experiences, health-risk behaviors, and medical complications during pregnancy and delivery. This information included maternal responses to open-ended questions about concerns or worries within the past year and feelings about the pregnancy. Multiple sera samples were collected from mothers throughout their pregnancies and archived at -20oC. Offspring were administered cognitive, behavioral, and psychological assessments at ages 5, 9, and 15. The present study will include 750 mothers and their offspring who have complete data at each time point. Serological analyses will be conducted on archived prenatal sera from the first and second trimesters of pregnancy in order to measure biomarkers of maternal stress during pregnancy (i.e. cortisol), maternal levels of inflammatory proteins, termed cytokines, (the soluble receptors for IL-1 and TNF- and the cytokines IL-8 and IL-6), and markers of fetal hypoxia (VEGF). Further, prospectively collected labor and delivery information will be used for additional measures of fetal hypoxia. In addition, the present study will qualitatively code stress-related themes from narratives acquired in response to the aforementioned open- ended questions and geocode neighborhood-level contextual factors for each subject. The specific aims are as follows: 1) to investigate the contributions of fetal exposure to maternal stress and stress hormones to risk of depression in adolescent offspring, 2) to investigate whether there are intermediate childhood emotional and behavioral phenotypes, as well as altered cognitive trajectories between fetal exposure to maternal stress during pregnancy and subsequent depression in adolescence, and 3) to investigate whether fetal exposure to elevated levels of maternal stress adds to or interacts with other pre- and perinatal complications to increase risk for neurodevelopmental sequelae and adolescent psychopathology. The proposed study is uniquely positioned to answer key questions about how prenatal risk factors operate within the neurodevelopmental course of depression. The present study has the potential to influence the development of early intervention and prevention strategies, as well as to identify early risk markers for subsequent difficulties in adolescence.